Health research often involves multiple outcomes (e.g., survival, disease progression)1.
Current Methods
Emerging Methods
Compare strategies for both clinical trial design and prediction modelling that treat outcomes independently, as composite endpoints, and via emerging methods.
SECOMBIT Trial: Phase II randomised; N ≈ 209 metastatic melanoma; 3 arms5,6.
Endpoints: Overall Survival (OS) and Progression Free Survival (PFS).
Covariates: Sites, Lactate Dehydrogenase (LDH), Tumour Mutational Burden (TMB), a genetic biomarker (JAK).
Baseline Summary Table (by Arm)
| A (N=69) |
B (N=69) |
C (N=68) |
|
|---|---|---|---|
| Sites | |||
| 1 - 2 | 43 (62.3%) | 40 (58.0%) | 42 (61.8%) |
| >= 3 | 26 (37.7%) | 29 (42.0%) | 26 (38.2%) |
| LDH | |||
| Normal | 41 (59.4%) | 39 (56.5%) | 47 (69.1%) |
| Elevated | 26 (37.7%) | 28 (40.6%) | 20 (29.4%) |
| Missing | 2 (2.9%) | 2 (2.9%) | 1 (1.5%) |
| TMB | |||
| < 10 | 20 (29.0%) | 17 (24.6%) | 18 (26.5%) |
| >= 10 | 8 (11.6%) | 8 (11.6%) | 12 (17.6%) |
| Missing | 41 (59.4%) | 44 (63.8%) | 38 (55.9%) |
| JAK | |||
| Wild Type (Normal) | 24 (34.8%) | 17 (24.6%) | 16 (23.5%) |
| Mutated | 5 (7.2%) | 7 (10.1%) | 14 (20.6%) |
| Missing | 40 (58.0%) | 45 (65.2%) | 38 (55.9%) |
Time-to-event analyses was conducted for Overall Survival (OS) and Progression-Free Survival (PFS) separately. Survival distributions are visualised using Kaplan–Meier plots. Cox proportional hazards models are fitted to estimate covariate-adjusted effects, and as a preliminary predictive modelling strategy.
Kaplan - Meier Plot
Log-rank tests
| Endpoint | Chi.square | df | p.value |
|---|---|---|---|
| OS | 2.80 | 2 | 0.2460 |
| PFS | 7.74 | 2 | 0.0208 |
| Variable | HR (95% CI) | p-value |
|---|---|---|
| ArmB | 0.98 (0.38–2.50) | 0.9590 |
| ArmC | 0.83 (0.33–2.07) | 0.6900 |
| Sites>= 3 | 2.02 (0.93–4.42) | 0.0764 |
| LDHElevated | 0.96 (0.43–2.15) | 0.9130 |
| TMB>= 10 | 0.72 (0.31–1.67) | 0.4480 |
| JAKMutated | 0.63 (0.24–1.63) | 0.3380 |
| Variable | HR (95% CI) | p-value |
|---|---|---|
| ArmB | 0.73 (0.30–1.77) | 0.4870 |
| ArmC | 1.03 (0.48–2.22) | 0.9470 |
| Sites>= 3 | 1.60 (0.80–3.20) | 0.1870 |
| LDHElevated | 1.14 (0.56–2.34) | 0.7150 |
| TMB>= 10 | 0.85 (0.40–1.78) | 0.6660 |
| JAKMutated | 0.41 (0.16–1.03) | 0.0571 |
Proportial Hazard Test
| Endpoint | PH.test.p.value |
|---|---|
| OS | 0.0581 |
| PFS | 0.0119 |
The code and datasets for this project can be viewed at our GitHub repository here: https://github.com/darshu-d/MSc-Research-project-